1. Nanoparticles for Nanomedicine Neil S. Forbes Nanotechnology Institute University of Massachusetts, Amherst July 24, 2009 University of Massachusetts Chemical Engineering

2. Targeted Delivery to Tumors

3. Many Different Length Scales 10cm 1cm 100 m 1 m

4. Relative Size of Nanoparticles Nanoparticle with a 2 nm core and an octanethiol functionalized monolayer

5. Making Gold Nanoparticles AuCl4- salts are reduced using NaBH4 in the presence of thiol capping ligands The core size of the particles formed can be varied from <1 nm to ~ 8 nm The surface functionality can be controlled through the choice of thiols

6. Fluorophores and Drugs Selectively Dissociate Inside Cells

7. Control of Surface Charge

8. Investigating Delivery Using Cylindroids 100 m Plug Well Plate Microscope Objective Cylindroid Viable Dead

9. Nanoparticles in Cylindroids

10. Nanoparticle Diffusion 4hrs 24hrs d c a x y b D×10 7 cm 2 /sec

11. Modeling Particle Diffusion

12. Predicting Behavior in Tumors

13. Delivery of Doxorubicin

14. How Does Particle Charge Affect Tissue Penetration? Transcellular Paracellular Cells A B

15. Engineering Approach: Targeted Intratumoral Therapy Quantify tumor microenvironments Develop vectors to target tumor quiescence Necrotic Quiescent Proliferating Therapeutic

16. Microenvironments in Cylindroids Viability Acridine Orange Scale bar is 100 µ m Kasinskas, Forbes. 2006. Biotech Bioeng, 94:710

17. Bacteria Accumulate in Mouse Tumors

18. Bacteria are Tiny Robot Factories Target specific molecular signals Can controllably produce therapeutics

19. Bacterial Accumulation in Cylindroids 100 m PQN Plug Well Plate Microscope Objective Cylindroid 96-well plate Culture Media Polycarbonate Lid Cylindroids mimic tumor microenvironments

20. Control of Cytotoxicity 1.Inject modified bacteria 2.Induce peptide with radiation

21. Tumor Growth and Mouse Survival PBS Control Bacteria Cytotoxic Bacteria PBS + 2Gy Control Bacteria + 2Gy Cytotoxic Bacteria + 2Gy Cytotoxic Bacteria Control Bacteria PBS Bacteria + Radiation Control + 2Gy PBS + 2Gy Median survival doubles from 14.0 to 26.0 days

22. Effect of Double Dose Delayed growth 30.3 days 30-day survival increased from 0% to 100%

23. Acknowledgements Graduate Students Adam St. Jean Charley Swofford Bhushan Toley Raja Venkatasubramanian Miaomin Zhang Undergraduate Students Brett Babin Jason Lee Marissa McGarry Alumni Dr. Sabha Ganai, MD PhD Surgical Oncology, Baystate Medical Center Dr. Rachel Kasinskas, PhD Dr. Byoung-jin Kim, PhD Colin Walsh Collaborators Michael A Henson, PhD Richard B Arenas, MD Vincent M Rotello, PhD Funding NIH, NSF Susan G. Komen For the Cure UMass Center for Biomedical Research Rays of Hope, Springfield, MA

25. Cells A BC